Osteosarcoma is an aggressive bone cancer that affects children and adolescents. Osteosarcoma is considered a disease of disrupted differentiation wherein tumor cells are unable to differentiate into proper bone-forming mature osteoblasts. Osteosarcoma is often advanced at presentation and current treatments consist primarily of chemotherapeutic regimens and surgery. Osteosarcoma has a high rate of recurrence and often leads to limb amputations in young patients. The survival rate for metastatic osteosarcoma remains around 30% and alternative treatments are badly needed for this devastating disease. In this collaborative study, we propose to test a novel approach for treating osteosarcoma by harnessing intrinsic multipotency features of the osteosarcoma cancer stem cells. Osteosarcomas arise from mesenchymal stem cells that normally have the ability to form bone and fat cells. Our differentiation therapy approach is to use agents that preferentially inhibit the growth of osteosarcoma cancer stem cells while steering them to become adipocytes. We will use a class of drugs, the TZDs, that are agonists for PPAR?, the master regulator of adipogenesis. Several TZDs are approved for their unrelated effect in insulin clearance and treatment of diabetes. We have found that TZDs can inhibit the growth of osteosarcoma cells and promote adipogenic differentiation. We will test the effects of TZD on primary mouse and human osteosarcoma cells in mice, and examine their effects on cells and tumors. In particular, we will determine whether the TZDs can activate genes needed for adipogenesis. If successful, this proposal will provide the basis for new strategies to treat osteosarcoma in the clinic.